Quinoline compounds and process of making same



Patented July 5, 1949 2,474,818

QUINOLINE COMPOUNDS AND PROCESS OF MAKING SAME Joseph H. Burckhalter, Detroit, Eldon M. Jones and Albert L. Rawlins, Grosse Pointe Woods, Frank H. Tendick, Grosse Pointe Park, and Walter F. Holcomb, Detroit, Mich., assignors to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application September 29, 1944,

Serial No. 556,496

12 Claims. (Cl. 260-286) 1 2 The inventionrelates to a class of new chemidesignated as compounds A and B. Compound cal compounds having the general formula for Ahas the general formula the free base: H

0 H 5 HaN-- 5 4 NH- M l o a I z 7 2 I L J L 3 N i J where M and X have the same significance as lo given above.

where Zn represents n substituents Z, n being 1, 2 or 3, and Z is a substituent of the class Compound]; has the generalformula' consisting of -NO2 substituted or unsubstituted Cl amino and groups hydrolyzable thereto, --OH,' 4 --CN, halogen, lower alkyl, lower hydroxy alkyl, 3 lower alkoxy, phenyl, and amino substituted 2 phenyl' b r 1 i m N M in the a ove ormula s a group n ei er the ortho or para position to the hydroxy group 32 has the same significance as given i fi m said group M itself havmg the It should also be understood that instead of having a chloro group at position 4, the inter- RI mediate B may have other halogen groups in this position.

R The condensation may be carried out by reacting equimolar portions of compounds A and in which R1 and R2 may be hydrogen, an alkyl B in a suitable solvent. The reaction may be group (saturated 'or unsaturated), containing carried out in alkaline, neutral or acid solution lto 4 carbon atoms, or a hydroxyalkyl group but preferably it is carried out in the presence containing 1 to. 4 carbon atoms; R1 and R2 may of a mineral acid. or may not be identical. The following specific examples are illustrative: X in the above formula represents hydrogen, Example 1 7 chlom 4 (3, ,diemylaminomethyl chlorin b omi hydroxy, lower alkoxy lower 4'-hydroryphenylammo) quinoline .alkyl (saturated or unsaturated) phenyl or it may be the same as M. These compounds are OH useful therapeutic agents and, in general, they I Q are characterized by their toxicity to protozoa, HNm, particularly plasmodia. Thesenew compounds may be used in the form of their salts of hydro- O] chloric acid, sulfuric acid, phosphoric acid, sulf- N amic acid, acetic acid, lactic acid, tartaric acid,, 2 t 1 t 4 acetylaminophenol l ni acid. citric id, nd alkyl sulfouic aci (64.0 g.) is refluxed with 128 cc. of concentrated or as the insoluble salt of methylene disalicylic 01 for one hour, The cooled ut is dacid. justed to pH 4 by adding 40% NaOH and 49.5 g. This application is a continu tion-inmar f of 4,7-dichloroquinoline in '50 cc. of alcohol is our copending application. Serial No. 539,990, added. The reaction mixture is heated for four filed June 12, 1944. now Patent No. 2,428,355, hours, diluted to 1500 cc. with boiling water, issued October 7,1947. and the free base precipitated by adding concen- The new compoundsof th invention may be trated ammonium hydroxide. This product is prepared by the condensation of certain interfiltered ofi', washed with water and acetone, then mediates which, for convenience, are herein recrystallized from Cellosolve. The 'Z-ch1oro-4.-

Example 2.7-chZoro-3- methyl (3' diethylaminomethyl 4'- hydrozyphenylamino) quinoline dihydrochloride Nil-Q01: on, Home A mixture of 23.6 g. of 2-diethylamlnomethyl- 4-acetylaminophenol, 50 cc. of concentrated H01, and 50 cc. of H20 is refluxed for 2 hours, then it is cooled and the pH adjusted to 4 by the addi-.- tion of 40% KOH. The solution is then treated with 20 3-methyl-4,7-dichloi-oquinoline and refluxed for 20 minutes. The clear solution is then cooled, alkalized with NH4OH, and extracted with ether. The extract is then washed with water, dried over MgSO4, and evaporated. The residue is dissolved in absolute ethanol and treated with alcoholic HCl. Upon standing, the solution deposits a solid hydrochloride. Thecompound has a melting point of 260 C. with decomposition.

Example 3. fi-methoxy- (3-diethylaminomethyl-4'-hydroa:yphenylamino) quinoline dihydrochloride 'NHQOB omo mNEe A mixture of 23.6 g. of 2-diethylaminomethyl- 4-acetylaminophenol, 50 cc. of concentrated HCl, and 50 cc. of is refluxed for 2 hours, then it is cooled and the pH adjusted to 4 by the addition of 40% KOH. The solution is then treated with 20 g. 4-chloro-6-methoxy quinoline and refluxed for 20 minutes. The clear solution is then cooled, alkelized with NH4OH, and extracted with ether. The extract is then washed with water. dried over MgSO4, and evaporated. The residue is dissolved in absolute ethanol and treated with alcoholic HCl. Upon standing, the solution deposits a solid hydrochloride. The compound decomposes at 270 C.

Other compounds of this invention may be prepared in a similar manner by condensing com pounds A and B. The following are representative examples of compound A:

1. 2-diethylaminomethyl-4-t-butyl 6 aminophenol 2. 2-diethylaminomethylA-amino 6 chlorophenol 3. 2-diethylaminomethyl-4-amino 6 methylphenol 4. 2-diethylamlnomethyl 4 amino 6 methoxyphenol 5. 2 diethylaminomethyl-l-arnino-6-hydroxyphenol 6. 2 diethylaminomethyl-4-chloro 6 aminophenol 7. 2-diethylaminomethyl-4-phenyl 6 aminophenol 8. 2-die-thylaminomethyl-4-amlno 6 phenylphenol 9. 2 diethylaminomethyl-4-amino 3,5,6 trimethylphenol nol 2 diethylaminomethyl 4 amino 5,6 d1- chlorophenol 2 diethyla'minomethyl 4 amino 3,6 dichlorophenol 2 diethylamlnomethyl 4 amino 3,5 dichlorophenol 2-diethy'laminomethyl 4 amino 3,5,6 trichlorophenol 2 diethy1aminomethy1-4-amino 6 bromophenol 2-diethylaminomethyl-4-amino 5 methyl- 6-chlorophenol 2 -diethylaminomethyl-3-methyl 4 amino- 6-chlorophenol 18. 2 diethylamlnomethyl-3-chloro 4 amino- S-methylphenol 19. 2 diethylaminomethyl-4-amino-5-methoxy- 6-chlorophenol 20. 2 diethylaminomethyl-3-methoxy-4-aminofi-chlorophenol 21. 2 diethylaminomethyl-3-chlor0 4 aminofi-methoxyphenol 22. 2 diethylaminomethyl-a-cyano 4 aminophenol 23. 2 diethylaminomethyl-4-amino 5 cyanophenol 24. 2 diethylamlnomethyl-4-amino 6 cyanophenol 25. 2 diethylaminomethyl 3 dlethylamino-4- aminophenol 26. 2-diethylaminornethyl-4-amlno 5 diethylaminophenol 27. 2-diethylaminomethyl-A-amino 6 diethylaminophenol 28. 2 diethylaminomethyl-4-amino-3,6-dimethoxyphenol 29. 2 diethylaminomethyl-4-amino-5,6-di1nethoxyphenol 30. Z-diethyIaminomethyl 4 amino-G-t-butylphenol 31. 2-diethyiaminomethyl-4-amino-5,6-dimethylphenol V I 32. 2-diethylamlnomethyl-4-amino-3,5-dimethylphenol 33. 2-diethylaminomethyl-4-amino-3,6-dimethylphenol 34. 2-diethylaminomethyl-3-methyl 4 aminofi-methoxyphenol 35. 2 diethylaminomethyl-3-methoxy-4-amino- S-methylphenol 36. 2-diethylaminomethyl-6-aminophenol 37. 2-dimethylaminomethyl-4-aminophenol 38. 2,4-bis-diethylaminomethyl-G-aminophenol 39. 2,G-bis-diethylaminomethyl-4-aminophenol 40. 2-phenyl-4-dlethylaminomethyl 6 amino- 1 phenol 41. 2-di(fl-hydroxyethyl) aminomethyl 4 aminophenol 42. 2-ethylaminomethyl-4-aminophenol The following are representative examples of compound B:

. 4-chloro-5,6-dimethoxy-quinoline 4-chloro-7-cyano-quinoline 4-chloro-fi-nitro-quinoline 4-chloro-6-amino-quinoiine 4-chloro-G-hydroxy-quinoline 4-chloro-G-p-hydroxyethoxy-quinollne 4-chloro-8-hydroxyethoxy-quinollne 4,5,8-trichloro-quinoline 4,6,8-trichloro-quinollne 10. 2,4-dich1oro-quinoline 11. 3,4-dichloro-quinoline 2-dicthylaminomethyl-kamlno 6 ailylphe- 12. 13. 14. 1B. 16. 17. 1s. 19. 2o.

59. so. 61. a2. 63. e4. 65.

'In addition to the compoundsspecifically re 5 4,6-dichloro-quinoline 4,8-dichloro-quinoline z-chloro-quinoline 2-chloro-5-nitro-quinoline 4,5,"l-trlchloro-quinoline 2,4-dichloro-quinoline 2-chloro-4-hydroxy-quinoline 4-chloro-2-hydroxy-quinoline 4-chloro-2-ethoxy-quinoline 4,6,7-trich1oro-quinoline 4-chloro-6-dimethylamino-quinoline 4-chloro-6-nitro-B-methoxy-quinoline 4-chloro-6,8-dimethyl-quinoline 4,6#dichloro-a-methyl-quinoline 4,6-dichloro-3-methyl-quinoline 4,8-dichloro-3-methyl-quinoiine 4,6-dichloro-8-methoxy-quinoline 4,7-dichloro-2-methoxy-quinoline 4,7-dichloro-3-methoxy-quinoline 4,7-dichloro-5-methoxy-quinoline 4,7-dichloro-5-hydroxy-quinoline 4,7-dichloro-6-methoxy-quinoline 4,7-dichloro-G-hydroxy-quinoline 4,7-dichloro-8-methoxy-quinoline 4-chloro-5-hydroxy-quinoline 4-chloro-fi-methoxy-quinoline 4-chloro-7-methoky-quinoline 4-chloro-B-methoxy-quinoline 4-chloro-6,7-dimethoxy-quinoline 4-chloro-5-amino-quinoline 4-chloro-7-amino-quinoline 4-chloro-8-amino-quinoline 4-chloro-7-bromo-quinoline 4-chloro-7-iodo-quinoline 4,6,7.8-tetrachloro-quinoline 4-chloro-l-hydroxy-quinoline -i-chloro-B-hydroxy-quinoline 2-phenyl 4-chloro-quinoline z-phenyl-4-ch1oro-B-methoxy-quinoline 2-pheny1-4-chloro-'7-methoxy-quinoline 2-phenyl-4fl-dichloro-quinoline 2-phenyl-4-chloro-6,'7-dimethyl-quinoline Z-phenyl-4-ch1oro-5,fiadimethoxy-quinoline 2-pheny1-4-chloro-7-cyano-quinoline 3,6-dimethyl-4-chloro-quinoline 3,7-dimethyl-4-chloro-quinoline 3,5-dimethyl-4-chloro quinoline 3,8-dimethyl-4-chloro-quinoline 3-methyl-4-ch1oro-5-methoxy-quinoline 3-m'ethyl-4-chloro-'7-methoxy-quinoline 3,G-dimethyl-4,7-dichloro-quinoline 2-n-propyl-4-ohloro-quinoiine 2-isopropyl-4-chloro-quinoline 4-chloro-8-ethyl-quinoline 4-chloro-8-n-propyl quinollne 4--chloro-S-isopropyl-quinoline t-chloro-'l-n--propyl-quinoline chloro 6- methoxy-quinoline l terred to under Examples 1 to 3, the following are representative examples of the class of combase, the invention includes the hereinbefore stated:

salts also as arms 1s minomethylphenylamino) quinoline 7-cyano-4-(4' hydroxy 3' diethylaminomethylphenylamino) quinoline fi-p-hydroxyethoxy-M' hydroxy 2,5' dimethyl 3' diethylaminomethylphenylamino) quinoline 6-chloro-4a(4'-hydroxy-2',5 dichloro 3'- diethylaminomethylphenylamino)' quinollne 2-chloro-4-(4'-hydroxy 3' diethylaminomethylphenylamino) quinoline j 6-dimethy1amino-4-(4' hydroxy 2',5' dimethoxy-3' diethylaminomethylphenylami- I no) quinoline 7-bromo-4-(4'-hydroxy-2'-methyl 5'-methoxy 3' diethylaminomethylphenylamino) quinoline 2-phenyl-6-methoky-4-( 4-hydroxy 3' diethylaminomethylphenylamino) quinoline 2-phenyl-7-methoxy-4 (4' hydroxy 2'- chloro-5'-methoxy-3' dlethylaminomethylphenylamino) quinoline 8-.B-hydroxyethoxy-4-(4'-hydroxy-5' chloro 3' a diethylaminomethylphenylamino) quinoline p 8-chloro-4-(4-hydroxy-5' methyl 3? diethylaminomethylphenylamino) quinoline 6,7,8-trich1oro-4-(2-hydroxy 3' diethylaminomethylphenylamino) quinoline 3-methy1-6-ch10ro-4-(4'-hyclroxy-2' cyano- 3'-diethylaminomethylphenylamino) quincline 3-methoxy-7-chloro-4-(4'-hydroxy-5' allyl 3'-diethylaminomethylphenylamino) quincline 8-methoxy-4-[4'-hydroxy-3'-di(p hydroxyethyl) aminomethylphenylamino] quinoline '5-methoxy-7-chloro-4-(4' hydroxy 2',5'-

6'-trichloro-3 diethylaminomethylphenylamino) quinoline 5-hydroxy-7-chloro-4 (4 hydroxy 2'- methyl-3' diethylaminomethylphenylamino) quinoline 7-chloro-8-methoxy-4-(4'-hydroxy 3' diethylaminomethylphenylamino) quinoline 7-methoxy-4-(4'-hydroxy 3' diethylaminomethylphenylamino) quinoline 8-methoxy-4-(4'-hydroxy 2' diethylamino 3' diethylaminomethylphenylamino) quinoline 'I-iodo-4-(4'-hydr0xy-3' diethylaminomethylphenylamino) quinoline 2-phenyi-7-chloro-4-(4'-hydroxy 3' diethylaminomethylphenylamino) quinoline 2-phenyl-6,7-dichloro-4 (4' hydroxy-3'- diethylaminomethylphenylamino) quinoline 3,8-dimethyl-4-(2'-hydroxy-3' phenyl 4'- diethylaminomethylphenylamino) quinoline Z-(p-diethylaminophenyl)-7-chloro4 (4'- hydroxy-3' diethylaminomethylphenylamino) quinoline The intermediate aminomethylaminophenols herein referred to as compounds A are usually prepared from aoylaminophenols by means of the Mannich reaction (Organic Reactions. John Wiley & Sons, Inc., New York, 1942,vo1. I, p. 303). This particular application of the reaction consists in the condensation of primary or secondary amines with formaldehyde and acylaminophenols having at least one unsubstituted position ortho or para to the phenolic hydroxyl. The resulting N-substituted aminomethylacylaminophenols are hydrolyzed with mineral acid to the The Magidson and Rubstov [J. Gen. Chem. (USSR),

7, 1896 (1937) i C. A., 32, 584 (1938)] or from the corresponding hydroxyquinolines which may be prepared by the method of Gould and Jacobs [J.

Am. Chem. 800., 61, 2890 (1939)] or by that of Theos J. Thompson [M. S. Thesis, University of Nebraska, July 24, 1942]. 1

For the preparation 01' the intermediate primary aminomethyl nitrophenols, the method of Einhorn [Ann., 343, 238 (1906)] involving a condensation of N-methylolbenzamide with nitrophenols is used. The desired aminomethylaminophenols are then obtained by reduction of the intermediate N-benzoylaminomethyl nitrophenols followed by acid hydrolysis.

For the preparation of quinoline intermediates with substituents in the 2-position such as the 2-phenyl derivatives, the method of Knorr [Ann., 245, 378 (1888)] involving the reaction of aniline or substituted anilines with benzoyl acetic ester is used. The 3-substituted-4-hydroxy quinolines are prepared by the method given in United States Patent No. 2,233,970.

Attention is directed to our copending applications wherein certain quinoline compounds related to those of the instant case are described and claimed as follows: Serial No. 576,900, filed Feb. 8, 1945; Serial Nos. 626,906, 626,907 and 626,- 908; all filed Nov. 5, 1945; and Serial No. 722,474, filed Jan. 16, 1947.

What we claim as our invention is:

1. A compound of the class consisting of a free base and its acid addition salts, said free base having the following formula NH-QOH HzNEt:

2. A compound of the class consisting of a free base and its acid addition salts, said free base havin the following. formula NH- OH CH; CHzNElZ:

Cl N having the following formula C H: O HzNE t:

4. A compound having the formula NHQ-OH ENE...

prepared by the method of 5 5. A compound having the formula Q CE; HaNEh 6. A compound having the formula NH-QOH cmo- HaNEtz 7. A compound'of the class consisting of a free base and its acid addition salts, said free base having the formula,

where Zn represents n substituents Z, n being an integer of the group consisting of one, two and three, Z is a substituent of the class consisting of NO2, unsubstituted amino, alkyl-substituted amino, groups hydrolyzable to amino, -OH, -CN, halogen, lower alkyl, lower alkoxy, lower hydroxy alkyl, phenyl and amino substituted phenyl, M is a group attached to the aryl nucleus in one of the positions ortho and para to the hydroxy group, the group M having the formula,

alkyl, lower alkylene, phenyl and M.

8. A compound of the class consisting of a free base and its acid addition salts, said free base having the formula where Zn represents 11. substituents Z, n being an integer of the group consisting of one, two and three, Z is a substituent of the class consisting of -NO:, unsubstituted amino, alkyl-substi-.

tuted amino, groups hydrolyzable to amino, -OH, --CN, halogen, lower alkyl, lower alkoxy, lower hydroxy alkyl, phenyl'and amino substituted phenyl, and-R1 and R2 areradicals containing 1 to 4 carbon atoms of the class consisting of saturated alkyl, unsaturated alkyl and hydroxy alkyl.

9. Process for preparing a compound having the formula,

which comprises condensing a compound having the formula L .l with a compound having the formula where Zn represents at substituents Z, n being an integer of the group consisting of one, two and three, Z is a. substituent of the class consisting of -NO2, unsubstituted amino, alkylsubstituted amino, groups hydrolyzable to amino,

-OH, -CN, halogen, lower alkyl, lower alkoxy, lower hydroxy alkyl, phenyl and amino substituted phenyl, M is a group attached to the and nucleus in one of the positions ortho and para to the hydroxy group, the group M having the formula,

NKQOH HzNEh which comprises condensing a compound of the formula NE: with a compound having the formula 11. Processfor preparing a compound of the formula,

NHQOH CH: HaNEh which comprises condensing a compound of the formula CHsNEh N11: with a compound having the formula 12. Process for preparing a compound of the formula,

NH'QOH HzNEh which comprises condensing a compound of the formula HzNEt:

with a compound having the formula JOSEPH H. BURCKHALTER. ELDON M. JONES. ALBERT L. RAWLINSt FRANK H. TENDICK. WALTER F. HOICOMB.

REFERENCES CITED The following references are of record in' the flle of this patent:

UNITED STATES PATENTS Number Name Date 1,891,980 Hartmann Dec. 27, 1932 1,896,461 Muth Feb. '1, 193: 1,902,103 Sehonhofer Mar. 21, 1938 FOREIGN PATENTS Number Country Date 533,691 Germany Sept, 23. 1981 

